It has become apparent from multiple studies that hepatitis C virus (HCV) infection is very indolent and that serious sequelae (cirrhosis, carcinoma) occur in less than 15 percent of persons during their first 20 years of infection. It is presumed that the proportion with severe outcomes will increase as the duration of followup increases and it may be that those infected at a young age will fare worse because they have 3 to 8 decades for HCV infection to evolve into overt liver disease. This study, conducted in collaboration with Children's National Medical Center (CNMC) has identified infants and children who were transfused at CNMC from 1983 to 1992, the decade just prior to second generation anti-HCV testing. 5546 children, who met eligibility criteria, were transfused at CNMC during this interval. The mean age at transfusion was 1 year (range, birth to 10.7 years). Thus far, 2668 children (49 percent) have been recalled and provided consent/assent. The mean age at testing was 11 years (range 4 to 17 years). Of the 1753 children fully tested for antibodies to HCV and hepatitis G virus (HGV), 36 (2.0 percent) are anti-HCV positive and 100 (5.7 percent) HGV RNA positive. The HCV and HGV prevalence in age-matched non-transfused controls are 0.3 and 6.3 percent, respectively. There is a significant association between HCV infection and transfusion, but the overall prevalence is lower than expected given that these children were transfused prior to HCV donor screening. The 36 HCV infected children have been followed a mean of 24 months. All are asymptomatic. The range of ALT is 29 to 140 IU/ml; 80 percent have at least one ALT value that exceeds 1.5 times the upper limit of normal. In an adjunctive study, liver biopsies have been performed on 25 children, 16 of whom are included in this transfusion look-back study. The average interval from transfusion to biopsy was 10.7 years. The histologic lesions were generally mild, but four (16 percent) had bridging fibrosis. None had cirrhosis. Duration of infection and age at infection did not appear to influence the extent of fibrosis. In the final analysis, this study will determine the minimal rate of transfusion-transmitted HCV and HGV infections in the decade before anti-HCV testing and will allow for an annualized incidence estimate and a determination of the national burden of transfusion-induced viral hepatitis in children. To date it appears that persistent infection and chronic liver disease are less common in children than adults, but continued long-term followup with serial liver biopsies is necessary before the true disease burden can be ascertained. This study will have major implications for anti-viral therapy programs and might serve to shift emphasis to pediatric populations where response rates may be higher and the long-term benefit greater.